This is the National phase application of PCT/EP9905686, filed Aug. 6, 1999.
The present invention relates to a process for the preparation of S-N,Nxe2x80x2-bis[2-hydroxy-1-(hydroxymethyl)-ethyl]-5-[(2-hydroxy-1-oxopropyl)-amino]-2,4,6-triiodo-1,3-benzenedicarboxamide of formula (I), more commonly known as Iopamidol, which is one of the world top compounds in the field of iodinated contrast agents, which process comprises a novel step for the synthesis of the intermediate S-N,Nxe2x80x2-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-5-[(2-(acetyloxy)-1-oxopropyl)-amino]-2,4,6-triiodo-1,3-benzenedicarboxamide of formula (II). 
The synthesis of Iopamidol was described first in GB 1.472.050 and it involves the steps represented in the following Scheme: 
and precisely the reaction of S-(xe2x88x92)-5-[[2-(acetyloxy)-1-oxopropyl]amino]-2,4,6-triiodo-1,3-benzenedicarboxylic acid dichloride of formula (III) dissolved in dimethylacetamide (DMAC) with a slight excess of 2-amino-1,3-propanediol (commonly named serinol) also dissolved in dimethylacetamide, in the presence of tributylamine to give the compound (II), S-N,Nxe2x80x2-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-5-[(2-(acetyloxy)-1-oxopropyl)amino]-2,4,6-triiodo-1,3-benzenedicarboxamide.
The ratio between compound (II), serinol and tributylamine, expressed in equivalents, is 1:2.5:2. The reaction is carried out at 50xc2x0 C. and, after some hours, the desired product is obtained in a 92% yield.
The work up of the reaction mixture, described in the cited Patent, comprises evaporating dimethylacetamide, suspending the oily residue in methylene chloride, taking up repeatedly the precipitate with hot methylene chloride.
The resulting residue is then hydrolysed to Iopamidol with NaOH and the resulting solution is subsequently purified from the salts by treatment with a cationic resin and an anionic one, then recrystallized from ethyl alcohol.
The main problems with this process are the following ones:
the distillation of the solvent under vacuum at the end of the reaction is a very troublesome operation from the industrial point of view, DMAC being a high boiling product (165xc2x0 C.);
the use of DMAC gives rise to the presence of N-[2-hydroxy-1-(hydroxymethyl)ethyl]-Nxe2x80x2-dimethyl-5-[(2-hydroxy-oxopropyl)amino]-2,4,6-triiodo-1,3-benzenedicarboxamide 
10 i.e. one of the seven impurities of Iopamidol described in Pharmeuropa, vol. 6, nxc2x04, Dececember 1994, p. 343-345, which is essentially ascribable to the production of dimethylamine by DMAC during the work up of the reaction;
furthermore, the use of such a high boiling solvent is troublesome and difficult as traces thereof remain in the recovered solid product, which traces must not, however, exceed 650 ppm (USP limit for Iopamidol).
A first attempt to replace DMAC consists in GB Patent 2,272,218 (priority Oct. 27, 1992), which only discloses the preparation of compound (II) by using solvents different from DMAC, i.e. acetone or lower alcohols (C1-C4), in the presence of a base, preferably tributylamine.
As recognized by the inventors themselves in GB patent application 2.311.524, which has been published subsequently and will be discussed in the following, Iopamidol obtained from intermediate (II), albeit having an acceptable purity level, also contained different impurities instead of impurity I.
The medical profession and the rules concerning the marketing authorizations of medicaments, require medicaments with extremely low impurities contents so as to minimize the related risks of side-effects or toxic effects for the patient.
In the case of the iodinated contrast agents such need is particularly justified as the total amount of product administered is many orders of magnitude higher than other medicaments. Only by way of example, the dose or opacifying agent injected can reach and even exceed 150 g.
In fact, the pharmacopoeia standards of Iopamidol have recently been modified, (Italian Pharmacopoeia IX, 3rd revision, 1994; US Pharmacopoeia XXIII, 5th revision, Nov. 15, 1996) in that Iopamidol should contain a maximum of 0.25% impurities.
Recently published GB patent application 2,311,524 (priority Mar. 29, 1996), discloses an alternative method for the preparation of Iopamidol with such purity characteristics.
GB 2,311,524 discloses the preparation of compound (I), using N-methylpyrrolidone as reaction solvent, in the presence of a base, preferably selected from serinol, tributylamine, triethylamine or an inorganic carbonate, and it claims a higher purity of the resulting compound (II) which favourably affects the final purity of Iopamidol.
The preferred process described comprises the reaction of compound (III) with serinol in N-methylpyrrolidone and in the presence of previously purified triethylamine or sodium carbonate. The subsequent treatment of the resulting crude through a battery of ion exchange resins (strongly cationic, weakly anionic, strongly anionic, weak anionic, as described in GB 2.287.024) gives the final compound Iopamidol, with a purity which apparently meets the pharmacopoeia standards.
It is therefore evident from the prior art the increasing need to avoid the use of DMAC, which would also be advantageous in terms of impurities present in Iopamidol while improving the carrying out of the industrial process.
Moreover, N-methylpyrrolidone belongs to the same class of dipolar aprotic solvents as DMAC and it has the same boiling point characteristics, and it is therefore difficult to be removed completely.
It has now surprisingly been found that Iopamidol can be prepared in accordance with the pharmacopoeia standards by the process of the invention comprising:
a novel method for the preparation of compound (II);
the easy transformation of the resulting compound (II) into Iopamidol, involving neither basic hydrolysis nor complex chromatographic treatments.
It is therefore the object of the present invention a process for the preparation of compound (I) comprising the formation of compound (II) by reaction of compound (III) in the presence of only serinol, without solvent, followed by hydrolysis of the acetate group.
It has surprisingly been found that the reaction can be carried out without solvent and without addition of a base, in particular tributylamine as in the prior art, thereby effectively solving the problems mentioned above connected with the presence of DMAC, while obtaining a final product with the purity characteristics in accordance with the pharmacopoeia standards.
As already described in international patent application WO 92/14539, it was already known from the prior art that the reaction can be carried out without a base, using more than 4 equivalents of serinol, which acts as binding agent of the hydrochloric acid formed during the reaction. The reaction was however carried out still in DMAC thus involving the above mentioned problems.
It has surprisingly been found that adding serinol in a molar ratio to compound (III) ranging from 6 to 25, preferably from 8 to 16, the use of a solvent to carry out the condensation reaction between compound (III) and serinol is no more necessary.
Moreover, the serinol excess allows to avoid the addition of a base for the subsequent hydrolysis of compound (II) to Iopamidol.
The temperature of the condensation reaction can range from 30xc2x0 C. to 70xc2x0 C., preferably from 38 to 55xc2x0 C.
The time of the condensation reaction can range from 24 to 100 h, preferably from 40 to 72 h.
At the end of the reaction between serinol and compound (III), monitored by HPLC analysis, the acetate group is hydrolysed by addition of water, preferably in amounts of 2 to 4 kg of water per mol of compound (III): the solution is already basic due to the presence of the serinol excess.
The temperature of the solution is suitably adjusted to 50-70xc2x0 C., preferably 55-65xc2x0 C., and kept for a time ranging from 1 to 8 h, preferably from 2 to 5 h. At the end the mixture is neutralized by addition of HCl.
Operating according to the process of the invention, the final reaction mixture containing compound (I), only contains: serinol, serinol hydrochloride, serinol acetate. The only cation present is therefore only serinol thus involving an improvement in the Iopamidol desalting and purification processes.
The absence of dipolar aprotic solvents in the final solution, which are conversely always present in the prior art, allows to purify compound (I) without use of rather expensive industrial apparatuses, such as the nanofiltration apparatus for the preliminary desalting (see WO 92/14539) and the removal of DMAC or the battery of columns first mentioned when using N-methylpyrrolidone (see GB 2,311,524).
The process of the present invention comprises a chromatographic purification on a conventional column comprising a solid phase selected from the group consisting of highly cross-linked macroporous styrene resins, preferably Amberlite(copyright) XAD 1600, 1600 T and 16 (Rohm and Haas) or equivalents thereof commercialized by other producers. The elution is carried out with water, washing until disappearance of the compound, monitored by UV analysis.
After concentrating the aqueous phase, desalting is carried out by a battery (arranged in series or in mixed bed) of a sulfonic strongly cationic resin, regenerated in the acidic form, and a secondary amine medium anionic resin, regenerated in OHxe2x88x92 form.
The preferred cationic resins are selected from the group consisting of: Dowex C 350, Amberjet 1200, Amberlite IR 120.
The preferred anionic resin is Relite MG 1.
The desalted solution is concentrated and purified by crystallization from a suitable solvent, as already known in literature (GB 1,472,050, GB 2,708,601, U.S. Pat. No. 5,689,002, WO 97/02235, EP 747344).
Iopamidol obtained by the process of the invention has an impurities content not higher than 0.18% by HPLC analysis, as described in Pharmacopoeia (see above). Neither DMAC from any previous steps for the preparation of compound (III), nor other solvents are found in amounts higher than the requirements of ICH (International Conference on Harmonization) for the presence of residual solvents in pharmaceuticals.
The absence of DMAC or other dipolar aprotic solvents allows to reduce the amount of the crystallization solvent to about one third compared with the prior art, in that the solvent entrainment effect by the dipolar aprotic solvent is no longer present.
Moreover the use of serinol as the base, besides removing the impurity I, reduces the risk of formation of S-N,Nxe2x80x2-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-5-amino-2,4,6-triiodo-1,3-benzenedicarboxamide of formula (IV) 
in which a free amino group is present, and that therefore belongs to the harmful class of aromatic amines, which is very difficult to remove from compound (I) once formed. The decrease in this by-product in the process of the present invention, is likely due to the lower basicity of serinol in the complementary hydrolysis reaction of the amide having lactic acid at the 5-position.